[Show abstract][Hide abstract] ABSTRACT: There is a substantial amount of evidence from animal models that early brain injury (EBI) may play an important role for secondary brain injury after aneurysmal subarachnoid hemorrhage (aSAH). Cerebral microdialysis (CMD) allows online measurement of brain metabolites including the pro-inflammatory-cytokine interleukin-6 (IL-6) and matrix-metalloproteinase-9 (MMP-9) which is indicative for disruption of the blood-brain-barrier.
Twenty-six consecutive poor-grade aSAH patients with multimodal neuromonitoring were analyzed for brain hemodynamic and metabolic changes including CMD-IL-6 and CMD-MMP-9 levels. Statistical analysis was performed using a generalized estimating equation with an autoregressive function.
The baseline metabolic central nervous system (CNS) profile revealed brain metabolic distress and an excitatory response which improved over the following 5 days (P <0.001). Brain tissue hypoxia (PbtO2 < 20 mmHg) was common (>60% of patients) in the first 24 hours of neuromonitoring and improved thereafter (P <0.05). Baseline CMD-IL-6 and CMD-MMP-9-levels were elevated in all patients (median = 4059 pg/ml, interquartile range (IQR) = 1316 to 12456 pg/ml and median = 851 pg/ml, IQR = 98 to 25860 pg/ml) and significantly decreased over the days (P <0.05). A higher pro-inflammatory response was associated with the development of delayed cerebral ischemia (P = 0.04), whereas admission disease severity and early brain tissue hypoxia were associated with higher CMD-MMP-9 levels (P <0.03). Brain metabolic distress and increased IL-6 levels were associated with poor functional outcome (mRS >3, P ≤0.01). All models were adjusted for probe location, aneurysm securing procedure and disease severity as appropriate.
Multimodal neuromonitoring techniques allow insight into pathophysiologic changes in the early phase after aSAH. The results may be used as endpoints for future interventions targeting early brain injury in poor-grade aSAH patients.
Critical Care 12/2015; 19(1). DOI:10.1186/s13054-015-0809-9 · 4.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Biomechanical investigation.
This study describes ex vivo evaluation of the range of motion (ROM) to characterize the stability and need for additional dorsal fixation after cervical single-level, two-level or multilevel corpectomy (CE) to elucidate biomechanical differences between anterior-only and supplemental dorsal instrumentation.
Twelve human cervical cadaveric spines were loaded in a spine tester with pure moments of 1.5 Nm in lateral bending (LB), flexion/extension (FE), and axial rotation (AR), followed by two cyclic loading periods for three-level corpectomies. After each cyclic loading session, flexibility tests were performed for anterior-only instrumentation (group_1, six specimens) and circumferential instrumentation (group_2, six specimens).
The flexibility tests for all circumferential instrumentations showed a significant decrease in ROM in comparison with the intact state and anterior-only instrumentations. In comparison with the intact state, supplemental dorsal instrumentation after three-level CE reduced the ROM to 12 % (±10 %), 9 % (±12 %), and 22 % (±18 %) in LB, FE, and AR, respectively. The anterior-only construct outperformed the intact state only in FE, with a significant ROM reduction to 57 % (±35 %), 60 % (±27 %), and 62 % (±35 %) for one-, two- and three-level CE, respectively.
The supplemental dorsal instrumentation provided significantly more stability than the anterior-only instrumentation regardless of the number of levels resected and the direction of motion. After cyclic loading, the absolute differences in stability between the two instrumentations remained significant while both instrumentations showed a comparable increase of ROM after cyclic loading. The large difference in the absolute ROM of anterior-only compared to circumferential instrumentations supports a dorsal support in case of three-level approaches.
European Spine Journal 08/2015; DOI:10.1007/s00586-015-4167-8 · 2.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We conducted a systematic review of the literature to evaluate the safety and efficacy of surgical treatment of previously coiled aneurysms.
A comprehensive review of the literature for studies on surgical treatment of previously coiled aneurysms was conducted. For each study, the following data were extracted: patient demographics, initial clinical status, location and size of aneurysms, time interval between initial/last endovascular procedure and surgery, surgical indications, and microsurgical technique. We performed subgroup analyses to compare direct clipping versus coil removal and clipping versus parent vessel occlusion, early (<4 weeks post-coiling) versus late surgery and anterior versus posterior circulation.
Twenty-six studies with 466 patients and 471 intracranial aneurysms were included. All of the studies were retrospective and non-comparative case-series. Patients undergoing direct clipping had lower perioperative morbidity (5.0 %, 95 % CI = 2.6-7.4 %) when compared to those undergoing coil removal and clipping (11.1 %, 95 % CI = 5.3-17.0 %) or parent vessel occlusion (13.1 %, 95 % CI = 4.6-21.6 %) (p = 0.05). Patients receiving early surgery (<4 weeks post-coiling) had significantly lower rates of good neurological outcome (77.1 %, 95 % CI = 69.3-84.8 %) when compared to those undergoing late surgery (92.1 %, 95 % CI = 89.0-95.2 %) (p < 0.01). There were higher rates of long-term neurological morbidity in the posterior circulation group (23.1 vs. 4.7 %, p < 0.01) as well as long-term neurological mortality (4.4 vs. 2.8 %, p < 0.01).
Our meta-analysis suggests that surgical treatment is safe and effective. Our data indicate that aneurysms that are amenable to direct clipping have superior outcomes. Late surgery was also associated with better clinical outcomes. Surgery of recurrent posterior circulation aneurysms was associated with high rates of morbidity and mortality. Given the characteristics of the included studies, the quality of evidence of this meta-analysis is limited.
[Show abstract][Hide abstract] ABSTRACT: Meningiomas are known to be associated with female sex hormones. Worsening neurological symptoms or newly diagnosed meningiomas have been described in the context of elevated levels of sex hormones, for example, in pregnancy. To the authors' knowledge, tumor shrinkage after the normalization of hormones has not been described, even if it is known that neurological deficits due to meningioma compression may improve after giving birth. A 32-year-old female patient presented with severe headache and vision disturbances at the end of her second pregnancy. Magnetic resonance imaging revealed an extended mass at the lateral left-sided sphenoid wing that was suspected to be a meningioma. After delivery, the patient's symptoms improved, and MRI obtained 2 months postpartum showed significant shrinkage of the lesion. Significant tumor shrinkage can occur after pregnancy. Thus, repeat imaging is indicated in these patients.
Journal of Neurosurgery 07/2015; DOI:10.3171/2014.12.JNS142112 · 3.74 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Previous studies have demonstrated gender differences in pain perception in quantitative sensory testing. Thus, we hypothesized that there are differences in men and women with lumbar disc herniation awaiting lumbar sequestrectomy. To elucidate the differences in pain perception between men and women, we carried out a prospective clinical monocentric trial using quantitative sensory testing.
With institutional ethical approval, patients with radiculopathy awaiting lumbar sequestrectomy were examined the day before surgery. Preoperative pain was assessed using quantitative sensory testing and a series of questionnaires including Beck Depression Inventory and a numeric rating scale (NRS) for back and leg pain. Statistical analysis was performed using the Kolmogorov-Smirnov test for normal distribution. The unpaired Student's t-test, Mann-Whitney U test, and Fisher's exact test were used to analyze intergroup differences in the clinical and demographic characteristics and in clinical outcome variables.
Fifty patients (20 women and 30 men) were included in the study. The groups did not differ in NRS for back and leg pain. Heat and pressure pain thresholds were found to be lower in women than in men (p≤0.05). Subgroup analyses revealed decreased wind-up ratio in male patients with prior periradicular steroid application (p≤0.05).
Our results clearly indicate that sex differences in pain perception not only exist in healthy subjects, but also in patients with lumbar disc herniation. Therefore, it is essential to provide different treatment modalities to women and men.
Journal of Women's Health 06/2015; DOI:10.1089/jwh.2014.5108 · 2.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background Cerebrospinal fluid (CSF) leaks are a well-known complication of transsphenoidal surgery. Several autologous and artificial grafts have been used to close the sellar floor in an attempt to prevent postoperative CSF rhinorrhea. Objective To evaluate and describe a sandwich technique to close the sellar floor using autologous bone, absorbable gelatin sponge, and coated collagen fleece. Methods We reviewed 50 consecutive patients between April 2010 and August 2011 who underwent transsphenoidal surgery ending with reconstruction of the sellar floor with a particular sandwich technique. Patients with an intraoperative CSF leak received an additional lumbar drain. Results There were no cases of CSF rhinorrhea at postoperative follow-up after 6 weeks and no revision surgery. Conclusion The proposed sandwich technique for closure of the sellar floor to the sphenoid sinus is a suitable alternative to autologous grafts and seems to be effective in preventing CSF rhinorrhea.
Georg Thieme Verlag KG Stuttgart · New York.
Journal of Neurological Surgery. Part A: Central European Neurosurgery 06/2015; DOI:10.1055/s-0035-1547357 · 0.61 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cell-based regenerative approaches have been suggested as primary or adjuvant procedures for the treatment of degenerated intervertebral disc (IVD) diseases. Our aim was to evaluate the regenerative and immunogenic properties of mildly and severely degenerated cervical nucleus pulposus (NP) cells with regard to cell isolation, proliferation and differentiation, as well as to cell surface markers and co-cultures with autologous or allogeneic peripheral blood mononuclear cells (PBMC) including changes in their immunogenic properties after 3-dimensional (3D)-culture. Tissue from the NP compartment of 10 patients with mild or severe grades of IVD degeneration was collected. Cells were isolated, expanded with and without basic fibroblast growth factor and cultured in 3D fibrin/poly (lactic-co-glycolic) acid transplants for 21 days. Real-time reverse-transcription polymerase chain reaction (RT-PCR) showed the expression of characteristic NP markers ACAN, COL1A1 and COL2A1 in 2D- and 3D-culture with degeneration- and culture-dependent differences. In a 5,6-carboxyfluorescein diacetate N-succinimidyl ester-based proliferation assay, NP cells in monolayer, regardless of their grade of degeneration, did not provoke a significant proliferation response in T cells, natural killer (NK) cells or B cells, not only with donor PBMC, but also with allogeneic PBMC. In conjunction with low inflammatory cytokine expression, analyzed by Cytometric Bead Array and fluorescence-activated cell sorting (FACS), a low immunogenicity can be assumed, facilitating possible therapeutic approaches. In 3D-culture, however, we found elevated immune cell proliferation levels, and there was a general trend to higher responses for NP cells from severely degenerated IVD tissue. This emphasizes the importance of considering the specific immunological alterations when including biomaterials in a therapeutic concept. The overall expression of Fas receptor, found on cultured NP cells, could have disadvantageous implications on their potential therapeutic applications because they could be the targets of cytotoxic T-cell activity acting by Fas ligand-induced apoptosis.
PLoS ONE 05/2015; 10(5):e0126954. DOI:10.1371/journal.pone.0126954 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Cerebral edema and delayed cerebral infarction (DCI) are common complications after aneurysmal subarachnoid hemorrhage (aSAH) and associated with poor functional outcome. Experimental data suggest that the amino acid taurine is released into the brain extracellular space secondary to cytotoxic edema and brain tissue hypoxia, and therefore may serve as a biomarker for secondary brain injury after aSAH. On the other hand, neuroprotective mechanisms of taurine treatment have been described in the experimental setting.
We analyzed cerebral taurine levels using high-performance liquid chromatography in the brain extracellular fluid of 25 consecutive aSAH patients with multimodal neuromonitoring including cerebral microdialysis (CMD). Patient characteristics and clinical course were prospectively recorded. Associations with CMD-taurine levels were analyzed using generalized estimating equations with an autoregressive process to handle repeated observations within subjects.
CMD-taurine levels were highest in the first days after aSAH (11.2 ± 3.2 µM/l) and significantly decreased over time (p
Neurocritical Care 04/2015; DOI:10.1007/s12028-015-0140-y · 2.44 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Cervical radiculopathy caused by spondylotic foraminal stenosis may require surgical treatment. Surgical options include anterior cervical foraminotomy and fusion or posterior cervical foraminotomy. Controversy remains regarding the preferable surgical approach. Pertinent clinical evidence is limited to low-quality observational reports. Therefore, treatment decisions are predominantly based on the individual surgeon’s preference and skill. The study objective is to evaluate the efficacy and safety of posterior foraminotomy in comparison to anterior foraminotomy with fusion for the treatment of spondylotic foraminal stenosis.
This is a multicenter randomized, controlled, parallel group superiority trial. A total of 88 adult patients are allocated in a ratio of 1:1. Sample size and power calculations were performed to detect the minimal clinically important difference of 14 points, with an expected standard deviation of 20 in the primary outcome parameter, Neck Disability Index, with a power of 80%, based on an assumed maximal dropout rate of 20%. Secondary outcome parameters include the Core Outcome Measures Index, which investigates pain, back-specific function, work disability, social disability and patient satisfaction. Changes in physical and mental health are evaluated using the Short Form-12 (SF-12) questionnaire. Moreover, radiological and health economic outcomes are evaluated. Follow-up is performed 3, 6, 12, 24, 36, 48 and 60 months after surgery. Major inclusion criteria are cervical spondylotic foraminal stenosis causing radiculopathy of C5, C6 or C7 and requiring decompression of one or two neuroforaminae. Study data generation (study sites) and data storage, processing and statistical analysis (Department of Medical Statistics, Informatics and Health Economics) are clearly separated. Data will be analyzed according to the intention-to-treat principle.
The results of the ForaC study will provide surgical treatment recommendations for spondylotic foraminal stenosis and will contribute to the understanding of its short- and long-term clinical and radiological postoperative course. This will hopefully translate into improvements in surgical treatment and thus, clinical practice for spondylotic foraminal stenosis.
Current Controlled Trials: ISRCTN82578069.
[Show abstract][Hide abstract] ABSTRACT: Traumatic brain injury (TBI) is an important cause of death and disability. Safety and pharmacodynamics of 4-amino-tetrahydrobiopterin (VAS203), a nitric oxide (NO)-synthase inhibitor, were assessed in TBI in an exploratory Phase IIa study (NOSynthase Inhibition in TRAumatic brain injury=NOSTRA). The study included 32 patients with TBI in six European centers. In a first open Cohort, eight patients received three 12-h intravenous infusions of VAS203 followed by a 12-h infusion-free interval over 3 days (total dose 15 mg/kg). Patients in Cohorts 2 and 3 (24) were randomized 2:1 to receive either VAS203 or placebo as an infusion for 48 or 72 h, respectively (total dose 20 and 30 mg/kg). Effects of VAS203 on intracranial pressure (ICP), cerebral perfusion pressure (CPP), brain metabolism using microdialysis, and the therapy intensity level (TIL) were end points. In addition, exploratory analysis of the extended Glasgow Outcome Score (eGOS) after 6 months was performed. Metabolites of VAS203 were detected in cerebral microdialysates. No significant differences between treatment and placebo groups were observed for ICP, CPP, and brain metabolism. TIL on day 6 was significantly decreased (p<0.04) in the VAS203 treated patients. The eGOS after 6 months was significantly higher in treated patients compared with placebo (p<0.01). VAS203 was not associated with hepatic, hematologic, or cardiac toxic effects. At the highest dose administered, four of eight patients receiving VAS203 showed transitory acute kidney injury (stage 2-3). In conclusion, the significant improvement in clinical outcome indicates VAS203-mediated neuroprotection after TBI. At the highest dose, VAS203 is associated with a risk of acute kidney injury.
KEYWORDS: NO-synthase inhibition; clinical trial; microdialysis; traumatic brain injury
[Show abstract][Hide abstract] ABSTRACT: Background:
Spontaneous intracerebral hemorrhage (ICH) is associated with high morbidity and mortality. Cortical spreading depolarizations (CSDs) increase brain matrix metalloproteinase (MMP)-9 activity leading to perihematomal edema expansion in experimental ICH.
The purpose of this report is to describe cerebral metabolic changes and brain extracellular MMP-9 levels in a patient with CSDs and perihematomal edema expansion after ICH.
We present a 66-year-old male patient with ICH who underwent craniotomy for hematoma evacuation. Multimodal neuromonitoring data of the perihematomal region revealed metabolic distress and increased MMP-9 levels in the brain extracellular fluid during perihematomal edema progression. At the same time, subdural electrocorticography showed clusters of CSDs, which disappeared after ketamine anesthesia on day six. Perihematomal edema regression was associated with decreasing cerebral MMP-9 levels.
This novel association between clusters of CSDs, brain metabolic distress, and increased MMP-9 levels expands our knowledge about secondary brain injury after ICH. The role of ketamine after this devastating disorder needs further studies.
Neurocritical Care 08/2014; 22(2). DOI:10.1007/s12028-014-0050-4 · 2.44 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Three-dimensional (3D) culture in porous biomaterials as well as stimulation with growth factors are known to be supportive for intervertebral disc cell differentiation and tissue formation. Unless sophisticated releasing systems are used, however, effective concentrations of growth factors are maintained only for a very limited amount of time in in vivo applications. Therefore, we investigated, if an initial boost with transforming growth factor-beta 1 (TGF-beta 1) is capable to induce a lasting effect of superior cartilaginous differentiation in slightly and severely degenerated human annulus fibrosus (AF) cells.Methods
Human AF tissue was harvested during surgical treatment of six adult patients with lumbar spinal diseases. Grading of disc degeneration was performed with magnet resonance imaging. AF cells were isolated and expanded in monolayer culture and rearranged three-dimensionally in a porous biomaterial consisting of stepwise absorbable poly-glycolic acid and poly-(lactic-co-glycolic) acid and a supportive fine net of non-absorbable polyvinylidene fluoride. An initial boost of TGF-beta 1 or TGF-beta 1 and hyaluronan was applied and compared with controls. Matrix formation was assessed at days 7 and 21 by (1) histological staining of the typical extracellular matrix molecules proteoglycan and type I and type II collagens and by (2) real-time gene expression analysis of aggrecan, decorin, biglycan, type I, II, III, and X collagens as well as of catabolic matrix metalloproteinases MMP-2 and MMP-13.ResultsAn initial boost with TGF-beta 1 or TGF-beta 1 and hyaluronan did not enhance the expression of characteristic AF matrix molecules in our 3D culture system. AF cells showed high viability in the progressively degrading biomaterial. Stratification by grade of intervertebral disc degeneration showed that AF cells from both, slightly degenerated, or severely degenerated tissue are capable of significant up-regulations of characteristic matrix molecules in 3D culture. AF cells from severely degenerated tissue, however, displayed significantly lower up-regulations in some matrix molecules such as aggrecan.Conclusions
We failed to show a supportive effect of an initial boost with TGF-beta 1 in our 3D culture system. This underlines the need for further investigations on growth factor releasing systems.
Journal of Orthopaedic Surgery and Research 08/2014; 9(1):73. DOI:10.1186/s13018-014-0073-8 · 1.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Introduction
Elevated brain potassium levels ([K+]) are associated with neuronal damage in experimental models. The role of brain extracellular [K+] in patients with poor-grade aneurysmal subarachnoid hemorrhage (aSAH) and its association with hemorrhage load, metabolic dysfunction and outcome has not been studied so far.
Cerebral microdialysis (CMD) samples from 28 poor grade aSAH patients were analyzed for CMD [K+] for 12 consecutive days after ictus, and time-matched to brain metabolic and hemodynamic parameters as well as corresponding plasma [K+]. Statistical analysis was performed using a generalized estimating equation with an autoregressive function to handle repeated observations of an individual patient.
CMD [K+] did not correlate with plasma [K+] (Spearman’s ρ = 0.114, P = 0.109). Higher CMD [K+] was associated with the presence of intracerebral hematoma on admission head computed tomography, CMD lactate/pyruvate ratio >40 and CMD lactate >4 mmol/L (P < 0.05). In vitro retrodialysis data suggest that high CMD [K+] was of brain cellular origin. Higher CMD [K+] was significantly associated with poor 3-month outcome, even after adjusting for age and disease severity (P < 0.01).
The results of this pilot study suggest that brain extracellular [K+] may serve as a biomarker for brain tissue injury in poor-grade aSAH patients. Further studies are needed to elucidate the relevance of brain interstitial K+ levels in the pathophysiology of secondary brain injury after aSAH.
[Show abstract][Hide abstract] ABSTRACT: Degenerative disc disease (DDD) of the cervical spine is common after middle age and can cause loss of disc height with painful nerve impingement, bone and joint inflammation. Despite the clinical importance of these problems, in current publications the pathology of cervical disc degeneration has been studied merely from a morphologic view point using magnetic resonance imaging (MRI), without addressing the issue of biological treatment approaches. So far a wide range of endogenously expressed bioactive factors in degenerative cervical disc cells has not yet been investigated, despite its importance for gene therapeutic approaches. Although degenerative lumbar disc cells have been targeted by different biological treatment approaches, the quantities of disc cells and the concentrations of gene therapeutic factors used in animal models differ extremely. These indicate lack of experimentally acquired data regarding disc cell proliferation and levels of target proteins. Therefore, we analysed proliferation and endogenous expression levels of anabolic, catabolic, ant-catabolic, inflammatory cytokines and matrix proteins of degenerative cervical disc cells in three-dimensional cultures. Preoperative MRI grading of cervical discs was used, then grade III and IV nucleus pulposus (NP) tissues were isolated from 15 patients, operated due to cervical disc herniation. NP cells were cultured for four weeks with low-glucose in collagen I scaffold. Their proliferation rates were analysed using 3-(4, 5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide. Their protein expression levels of 28 therapeutic targets were analysed using enzyme-linked immunosorbent assay. During progressive grades of degeneration NP cell proliferation rates were similar. Significantly decreased aggrecan and collagen II expressions (P<0.0001) were accompanied by accumulations of selective catabolic and inflammatory cytokines (disintegrin and metalloproteinase with thrombospondin motifs 4 and 5, matrix metalloproteinase 3, interleukin-1β, interleukin-1 receptor) combined with low expression of anti-catabolic factor (metalloproteinase inhibitor 3) (P<0.0001). This study might contribute to inhibit inflammatory catabolism of cervical discs.
PLoS ONE 05/2014; 9(5):e96870. DOI:10.1371/journal.pone.0096870 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recent evidence suggests axonal injury after aneurysmal subarachnoid haemorrhage (aSAH). The microtubule-associated protein, tau, has been shown to be elevated in the cerebrospinal fluid after aSAH, however, brain extracellular tau levels and their relation to long-term neurological and cognitive outcomes have not been investigated.
Serial cerebral microdialysis (CMD) samples were collected from 22 consecutive aSAH patients with multimodal neuromonitoring to determine CMD-total-tau by ELISA. CMD-total-tau was analysed considering other brain metabolic parameters, brain tissue oxygen tension (PbtO2), and functional and neuropsychological outcome at 12 months. All outcome models were analysed using generalised estimating equations with an autoregressive working correlation matrix to account for multiple measurements of brain extracellular proteins per subject.
CMD-total-tau levels positively correlated with brain extracellular fluid levels of lactate (r=0.40, p<0.001), glutamate (r=0.45, p<0.001), pyruvate (r=0.26, p<0.001), and the lactate-pyruvate ratio (r=0.26, p<0.001), and were higher in episodes of hypoxic (PbtO2<20 mm Hg) brain extracellular lactate elevation (>4 mmol/L) (p<0.01). More importantly, high CMD-total-tau levels were associated with poor functional outcome (modified Rankin Scale ≥4) 12 months after aSAH even after adjusting for disease severity and age (p=0.001). A similar association was found with 3/5 neuropsychological tests indicative of impairments in cognition, psychomotor speed, visual conceptualisation and frontal executive functions at 1 year after aSAH (p<0.01).
These results suggest that CMD-total tau may be an important biomarker for predicting long-term outcome in patients with severe aSAH. The value of axonal injury needs further confirmation in a larger patient cohort, preferably combined with advanced imaging techniques.
Journal of neurology, neurosurgery, and psychiatry 04/2014; 86(1). DOI:10.1136/jnnp-2013-307326 · 6.81 Impact Factor